The long-acting integrase inhibitor GSK744 protects macaques from repeated intravaginal SHIV challenge

Radzio, Jessica; Spreen, William; Yueh, Yun Lan; Mitchell, James; Jenkins, Leecresia; Garcı́a-Lerma, J. Gerardo; Heneine, Walid

doi:10.1126/scitranslmed.3010297

Cited by 69 publications

(73 citation statements)

References 22 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The relevance of PTM vaginal physiology has allowed researchers to assess in this species the impact of factors such as coinfections and contraceptive use on susceptibility to vaginal infection [29*,30], and to evaluate modalities to prevent vaginal virus transmission, including microbicides and other pharmacologic interventions [31–34], all while accounting for menstrual cycle phases [30,35,36*–38]. However, within-species comparisons of intravaginal and intrarectal challenges using PTMs may be confounded by the higher levels of baseline immune activation associated with elevated intestinal permeability and microbial translocation in the absence of infection in PTMs when compared with RMs [39].…”

Section: Nhp Host Speciesmentioning

confidence: 99%

Nonhuman primate models for the evaluation of HIV-1 preventive vaccine strategies

Prete

Lifson

Keele

2016

Current Opinion in HIV and AIDS

View full text Add to dashboard Cite

Purpose of review Nonhuman primate (NHP) models of AIDS are powerful systems for evaluating HIV vaccine approaches in vivo. Authentic features of HIV-1 transmission, dissemination, target cell tropism, and pathogenesis, and aspects of anti-HIV-1 immune responses, can be recapitulated in NHPs provided the appropriate specific model parameters are considered. Here, we discuss key model parameter options and their implications for HIV-1 vaccine evaluation. Recent findings With the availability of several different NHP host species/subspecies, different challenge viruses and challenge stock production methods, and various challenge routes and schema, multiple NHP models of AIDS exist for HIV vaccine evaluation. The recent development of multiple new challenge viruses, including chimeric simian-human immunodeficiency viruses (SHIVs) and simian immunodeficiency virus (SIV) clones, improved characterization of challenge stocks and production methods, and increased insight into specific challenge parameters have resulted in an increase in the number of available models and a better understanding of the implications of specific study design choices. Summary Recent progress and technical developments promise new insights into basic disease mechanisms and improved models for better preclinical evaluation of interventions to prevent HIV transmission.

show abstract

Section: Nhp Host Speciesmentioning

confidence: 99%

Nonhuman primate models for the evaluation of HIV-1 preventive vaccine strategies

Prete

Lifson

Keele

2016

Current Opinion in HIV and AIDS

View full text Add to dashboard Cite

show abstract

“…In low dose challenge models designed to more closely mimic HIV-1 transmission in humans, macaques administered CAB LA as PrEP were completely protected from repeated intrarectal [14] or intravaginal [15] SHIV162P3 challenges. Additionally, in a female rhesus macaque model utilizing Depo-Provera to thin the cervicovaginal epithelium to increase the probability of infection, CAB LA protected 6 of 8 female macaques from repeated high-dose intravaginal challenges [16].…”

Section: Introductionmentioning

confidence: 99%

Cabotegravir long acting injection protects macaques against intravenous challenge with SIVmac251

Andrews

Bernard

Poon

et al. 2017

Aids

View full text Add to dashboard Cite

Objective We evaluated the effectiveness of cabotegravir (CAB; GSK1265744 or GSK744) long-acting (LA) as pre-exposure prophylaxis (PrEP) against intravenous SIV challenge in a model that mimics blood transfusions based on the per-act probability of infection. Design CAB LA is an InSTI formulated as a 200 mg/mL injectable nanoparticle suspension that is an effective pre-exposure prophylaxis (PrEP) agent against rectal and vaginal SHIV transmission in macaques. Methods Three groups of rhesus macaques (n=8/group) were injected intramuscularly with CAB LA and challenged intravenously with 17 AID50 SIVmac251 on week 2. Group 1 was injected with 50 mg/kg on week 0 and 4 to evaluate the protective efficacy of the CAB LA dose used in macaque studies mimicking sexual transmission. Group 2 was injected with 50 mg/kg on week 0 to evaluate the necessity of the second injection of CAB LA for protection against intravenous challenge. Group 3 was injected with 25 mg/kg on week 0 and 50 mg/kg on week 4 to correlate CAB plasma concentrations at the time of challenge with protection. Five additional macaques remained untreated as controls. Results CAB LA was highly protective with 21 of the 24 CAB LA-treated macaques remaining aviremic, resulting in 88% protection. The plasma CAB concentration at the time of virus challenge appeared to be more important for protection than sustaining therapeutic plasma concentrations with the second CAB LA injection. Conclusions These results support the clinical investigation of CAB LA as PrEP in people who inject drugs.

show abstract

“…Median individual tissue:plasma drug concentration ratios ranged from 16 to 25% in the female genital tract and were 8% in rectal tissue in men suggesting that at the dose tested the formulation would fall short as a PrEP agent. Furthermore, a recent study conducted in rhesus macaques showed that two IM doses 1 month apart protected eight out of eight animals from multiple rectal exposures to simian/human immunodeficiency virus (SHIV), while all eight animals receiving placebo injections acquired infection [147–149]. …”

Section: Introductionmentioning

confidence: 99%

Drug delivery strategies and systems for HIV/AIDS pre-exposure prophylaxis and treatment

Nelson

Zhang

Ganapathi

et al. 2015

Journal of Controlled Release

View full text Add to dashboard Cite

The year 2016 will mark an important milestone - the 35th anniversary of the first reported cases of HIV/AIDS. Antiretroviral Therapy (ART) including Highly Active Antiretroviral Therapy (HAART) drug regimens is widely considered to be one of the greatest achievements in therapeutic drug research having transformed HIV infection into a chronically managed disease. Unfortunately, the lack of widespread preventive measures and the inability to eradicate HIV from infected cells highlight the significant challenges remaining today. Moving forward there are at least three high priority goals for anti-HIV drug delivery (DD) research: (1) to prevent new HIV infections from occurring, (2) to facilitate a functional cure, i.e., when HIV is present but the body controls it without drugs and (3) to eradicate established infection. Pre-exposure Prophylaxis (PrEP) represents a significant step forward in preventing the establishment of chronic HIV infection. However, the ultimate success of PrEP will depend on achieving sustained antiretroviral (ARV) tissue concentrations and will require strict patient adherence to the regimen. While first generation long acting/extended release (LA/ER) DDS currently in development show considerable promise, significant DD treatment and prevention challenges persist. First, there is a critical need to improve cell specificity through targeting in order to selectively achieve efficacious drug concentrations in HIV reservoir sites to control/eradicate HIV as well as mitigate systemic side effects. In addition, approaches for reducing cellular efflux and metabolism of ARV drugs to prolong effective concentrations in target cells need to be developed. Finally, given the current understanding of HIV pathogenesis, next generation anti-HIV DDS need to address selective DD to the gut mucosa and lymph nodes. The current review focuses on the DDS technologies, critical challenges, opportunities, strategies, and approaches by which novel delivery systems will help iterate towards prevention, functional cure and eventually the eradication of HIV infection.

show abstract

The long-acting integrase inhibitor GSK744 protects macaques from repeated intravaginal SHIV challenge

Cited by 69 publications

References 22 publications

Nonhuman primate models for the evaluation of HIV-1 preventive vaccine strategies

Nonhuman primate models for the evaluation of HIV-1 preventive vaccine strategies

Cabotegravir long acting injection protects macaques against intravenous challenge with SIVmac251

Drug delivery strategies and systems for HIV/AIDS pre-exposure prophylaxis and treatment

Contact Info

Product

Resources

About